chr5-83111026-A-G

Variant names:

• chr5-83111026-A-G
• rs1746416323
• NM_003401.5:c.140-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_003401.5(XRCC4):​c.140-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000011 in 1,450,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: XRCC4 NM_003401.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.00
• Publications: 0 publications found

Genes affected

XRCC4 (HGNC:12831): (X-ray repair cross complementing 4) The protein encoded by this gene functions together with DNA ligase IV and the DNA-dependent protein kinase in the repair of DNA double-strand breaks. This protein plays a role in both non-homologous end joining and the completion of V(D)J recombination. Mutations in this gene can cause short stature, microcephaly, and endocrine dysfunction (SSMED). Alternate transcript variants such as NM_022406 are unlikely to be expressed in some individuals due to a polymorphism (rs1805377) in the last splice acceptor site. [provided by RefSeq, Oct 2019]

XRCC4 Gene-Disease associations (from GenCC):

• short stature, microcephaly, and endocrine dysfunction

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• microcephalic primordial dwarfism-insulin resistance syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.17512438 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.7, offset of 12, new splice context is: tcccatggtttctgaatcAGaga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 5-83111026-A-G is Pathogenic according to our data. Variant chr5-83111026-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2582370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003401.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	NM_003401.5	MANE Select	c.140-2A>G		splice_acceptor intron	N/A	NP_003392.1	Q13426-2
	XRCC4	NM_001318012.3		c.140-2A>G		splice_acceptor intron	N/A	NP_001304941.1	Q13426-1
	XRCC4	NM_022406.5		c.140-2A>G		splice_acceptor intron	N/A	NP_071801.1	Q13426-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	ENST00000396027.9	TSL:5 MANE Select	c.140-2A>G		splice_acceptor intron	N/A	ENSP00000379344.4	Q13426-2
	XRCC4	ENST00000511817.1	TSL:1	c.140-2A>G		splice_acceptor intron	N/A	ENSP00000421491.1	Q13426-1
	XRCC4	ENST00000282268.7	TSL:1	c.140-2A>G		splice_acceptor intron	N/A	ENSP00000282268.3	Q13426-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1450158 Hom.: 0 Cov.: 30 AF XY: 0.0000125 AC XY: 9 AN XY: 721128

African (AFR) AF: 0.00 AC: 0 AN: 32674

American (AMR) AF: 0.00 AC: 0 AN: 41424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25784

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.00 AC: 0 AN: 83016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1108896

Other (OTH) AF: 0.00 AC: 0 AN: 59914

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Short stature, microcephaly, and endocrine dysfunction (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		6.0
GERP RS		5.6
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.87		Position offset: 14
DS_AL_spliceai		0.99		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1746416323; hg19: chr5-82406845;